Alternative titles; symbols
HGNC Approved Gene Symbol: KRT14
SNOMEDCT: 239084001, 239088003, 254179000, 294705005;
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:41,582,279-41,586,895 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Dermatopathia pigmentosa reticularis | 125595 | Autosomal dominant | 3 |
| Epidermolysis bullosa simplex 1A, generalized severe | 131760 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 1B, generalized intermediate | 131900 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 1C, localized | 131800 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 1D, generalized, intermediate or severe, autosomal recessive | 601001 | Autosomal recessive | 3 | |
| Naegeli-Franceschetti-Jadassohn syndrome | 161000 | Autosomal dominant | 3 |
KRT14 belongs to a large group of acidic type I keratins that interact with basic type II keratins to form the 8-nm cytoskeletal filaments of epithelial cells. Both type I and type II keratins have a central alpha-helical domain of over 300 amino acids that mediates keratin interaction. KRT14 is expressed in the basal layer of stratified squamous epithelia, including epidermis (summary by Albers and Fuchs (1987) and Rosenberg et al. (1988)).
Albers and Fuchs (1987) constructed a complete human K14 cDNA using a partial cDNA isolated by Hanukoglu and Fuchs (1982) and a genomic clone described by Marchuk et al. (1984, 1985). The deduced 472-amino acid protein has an N-terminal domain, 4 helical domains, and a short C-terminal tail. Helical domain-4 has a highly conserved sequence (TYRRLLEGE) found in nearly all intermediate filament proteins.
Rosenberg et al. (1988) mapped the keratin-14 gene to chromosome 17. Rosenberg et al. (1991) stated that the KRT14 and KRT16 (148067) genes, as well as a yet-unidentified keratin gene, had been localized to chromosome 17q12-q21. Another cluster of genes located at chromosome 17p12-p11 contained a nonfunctional gene for KRT16 and 2 genes for KRT14, at least 1 of which was found to be a pseudogene.
Milisavljevic et al. (1996) analyzed P1 clones containing multiple acidic keratin genes using restriction analysis and Southern blot hybridization with PCR-amplified probes specific for functional human keratin genes 15 (148030), 17 (148069), and 19 (148020). Their results showed that there are 2 clusters of acidic keratin loci on chromosome 17q12-q21, very closely linked to each other within a 55-kb region. The genes were organized 5-prime to 3-prime in the following order: K19--K15--K17--K16--K14. Between K15 and K17 at least 1 additional, unidentified keratin gene was present.
PtK2 potoroo kidney epithelial cells express only the type I keratin K18 (148070) and the type II keratin K8 (148060). Albers and Fuchs (1987) showed that epitope-tagged human K14 was incorporated into endogenous keratin filaments along with K18 and K8 in PtK2 cells. Truncation of K14 after helical domain-4 had no effect on incorporation of K14 into filaments. However, progressive truncation of K14 within helix-4 resulted in a correspondingly progressive disruption of filament structure and accumulation of the truncated protein into cytoplasmic aggregates. The integrity of all other cytoskeletal structures remained intact. Albers and Fuchs (1987) concluded that the mutant protein both interfered with the formation of new keratin filaments and disrupted the existing keratin cytoskeleton.
Langbein et al. (2005) examined the expression of several keratins in eccrine sweat gland and in plantar epidermis. In the sweat gland, KRT14 was expressed in lower portions of the duct and in the deeper secretory region of the gland, but not in the superficial region. In plantar epidermis, KRT14 was expressed only in the basal layer and in part of the lower suprabasal layer.
In mice, Takeo et al. (2013) showed that nail stem cells (NSCs) reside in the proximal nail matrix and are defined by high expression of keratin-14, keratin-17, and KI67 (MKI67; 176741). The mechanisms governing NSC differentiation are coupled directly to their ability to orchestrate digit regeneration. Early nail progenitors undergo Wnt (see 164820)-dependent differentiation into the nail. After amputation, this Wnt activation is required for nail regeneration and also for attracting nerves that promote mesenchymal blastema growth, leading to the regeneration of the digit. Amputations proximal to the Wnt-active nail progenitors result in failure to regenerate the nail or digit. Nevertheless, beta-catenin (116806) stabilization in the NSC region induced their regeneration. Takeo et al. (2013) concluded that their results established a link between nail stem cell differentiation and digit regeneration, and suggested that NSCs may have the potential to contribute to the development of novel treatments for amputees.
Epidermolysis Bullosa Simplex
In a family with at least 16 affected individuals in 5 generations with localized epidermolysis bullosa simplex (EBS1C; 131800), Chen et al. (1993) identified a heterozygous mutation in the KRT14 gene (148066.0005).
Although all previous mutations identified in the KRT14 and KRT5 genes behaved as dominant-negatives with an autosomal dominant pattern of the clinical disorder, Hovnanian et al. (1993) described a French family in which 2 children with unaffected first-cousin parents had EB simplex (EBS1D; 601001) and homozygosity for a glu144-to-ala mutation (148066.0004) which was present in heterozygous state in both parents.
In a large 3-generation Irish family (TCDG) with the Koebner form of EBS (EBS1B; 131900), Humphries et al. (1993) identified heterozygosity for a missense mutation in the KRT14 gene (M272R; 148066.0007). Humphries et al. (1996) identified 2 more large Irish families with localized EBS and missense mutations in the KRT5 gene: M327T (148040.0004) in family TCDM, and N193K (148040.0007) in family TCDN. Noting that they knew of no other large families with EBS in the Irish population, Humphries et al. (1996) concluded that the M272R and N193K mutations in KRT5, together with the M272R variant in KRT14, likely accounted for most cases of dominant localized epidermolysis bullosa simplex in Ireland.
Chan et al. (1994) analyzed a very rare case of severe recessive epidermolysis bullosa simplex (EBS1D; 601001) in which the patient lacked a discernible keratin filament network in basal epidermal cells. Genetic analyses demonstrated homozygosity for a point mutation in the KRT14 gene (Y204X; 148066.0006) that yielded a premature termination codon in the major basal type I keratin gene and caused complete ablation of KRT14. The consanguineous parents were clinically normal, each harboring 1 copy of the null KRT14 mutation. Analysis of cultured keratinocytes revealed that the loss of KRT14 was not compensated for by the upregulation of other type I keratins. Thus, the cell fragility resulted from lack of an extensive basal keratin network.
Chen et al. (1995) systematically screened genomic sequences of KRT14 for mutations in patients of 49 apparently independent EBS kindreds using SSCP analysis. Most affected individuals were identified through assistance of the National EB Registry or through DEBRA of America, a genetic support group. KRT14 mutations were found in 10 of the families. The 10 mutations were clustered at 3 sites--the ends of the helices and the L12 linker region, where previous, more limited studies had identified mutations. Early onset of blistering in these 10 families was correlated with more widespread distribution of cutaneous mutations. Those with early onset of blisters (e.g., by age 1 week) had generalized disease; those with the later onset (e.g., after several months to 2 years) had blisters predominantly at acral sites. As in other families, patients with substitution of arg125 (148066.0002, 148066.0003) all had generalized blistering (EBS1A; 131760). Chen et al. (1995) reported a family with an arg125-to-ser mutation in which the proband had onset at 2 days of age. Generalized blistering was also present in a kindred with a gln120-to-arg mutation, giving onset in the first week of life. Chen et al. (1995) stated that they were aware of formal publication of mutations in either KRT5 or KRT14 in 22 apparently independent kindreds (7 in KRT5 and 15 in KRT14). They discussed the reason that mutation was identified in only 10 of the 49 kindreds.
In a 3-year-old boy (family 1) with generalized severe EBS (EBS1A) and a hoarse cry, Cummins et al. (2001) identified heterozygosity for a de novo occurrence of the previously reported M119T mutation in the KRT14 gene (148066.0009). In addition, the authors studied a 3-generation family with the Koebner type of EBS (EBS1B; family 2), Cummins et al. (2001) and identified heterozygosity for a missense mutation in the KRT14 gene (M119V; 131760.0022) that segregated with disease.
In a 31-year-old Japanese woman with the Koebner type of EBS, Gu et al. (2002) sequenced the KRT5 and KRT14 genes, and identified heterozygosity for a nonsense mutation in the KRT14 gene (E411X; 131760.0023). DNA was unavailable from her affected sons for analysis, but the mutation was not found in 50 unrelated control DNA samples.
In 2 French boys with generalized severe EB simplex, who developed marked palmoplantar keratoderma in the first months of life, Titeux et al. (2006) identified heterozygosity for the recurrent M119T substitution in the KRT14 gene (148066.0009), which occurred de novo in both probands. In a third French boy with severe EBS but less severe involvement of palms and soles, the authors identified a 1-bp deletion in KRT14 (148066.0024).
In a Scottish proband with EBS limited to the hands and feet, Rugg et al. (2007) identified heterozygosity for a missense mutation in the KRT14 gene (I377T; 148066.0021).
In a 15-year review of all infants born with generalized severe EBS and notified to the National Health Service of the UK, Sathishkumar et al. (2016) identified 37 cases. Genetic analysis in 33 of those cases showed KRT5 mutations in 17, KRT14 mutations in 15, and mutations in both KRT5 and KRT14 in 1 patient. Patients who were heterozygous for KRT14 mutations included 2 with the recurrent R125C variant (148066.0002), 4 with the recurrent R125H variant (148066.0003), and 2 with the N123S variant (148066.0018); 1 patient was heterozygous for R125H in KRT14 and an R471C variant in KRT5.
From a cohort of Iranian patients with clinical presentations and immunoepitope mapping suggestive of EBS, Vahidnezhad et al. (2016) identified 4 families with heterozygous mutations in the KRT5 gene and 7 families with mutations in KRT14. Homozygous KRT14 variants were present in 3 families, whereas heterozygous KRT14 variants segregated in 4 families, 2 of which exhibited severe disease (see, e.g., 148066.0020). One of the probands with severe disease (family 7) was reported to have digenic inheritance, with a heterozygous variant in KRT5 as well as KRT14. The remaining 2 heterozygous families exhibited localized disease; in 1 of them (family 9), some affected individuals who were born of consanguineous unions exhibited more generalized lesions and were found to be homozygous for the segregating variant (I377T; 148066.0021).
In an Italian male infant with generalized severe EB simplex and a hoarse cry, Diociaiuti et al. (2020) identified heterozygosity for the recurrent R125C mutation in the KRT14 gene (148066.0002).
Other Disorders
Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000) and dermatopathia pigmentosa reticularis (DPR; 125595) are 2 closely related autosomal dominant ectodermal dysplasia syndromes that clinically share complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation, thickening of the palms and soles (palmoplantar keratoderma), abnormal sweating, and other subtle developmental anomalies of the teeth, hair, and skin. Lugassy et al. (2006) studied one family with DPR and 4 families with NFJS. Both disorders map to 17q11.2-q21 (Whittock et al., 2000; Sprecher et al., 2002), which supported the suggestion that the disorders are allelic. Lugassy et al. (2006) refined the mapping of NFJS/DPR, finding a maximum lod score of 8.3 at marker D17S800 at a recombination fraction of 0.0. The disease interval was found to harbor 230 genes, including a large cluster of keratin genes. Heterozygous nonsense or frameshift mutations in KRT14 were found to segregate with the disease traits in all 5 families.
Fuchs and Coulombe (1992) noted that all point mutations identified to that time in patients with epidermolysis bullosa simplex (EBS) occurred in the rod domain of either the keratin-14 or keratin-5 protein, consistent with the dominant-negative behavior of most rod domain mutations and the autosomal dominant transmission of the disorder in most EBS families. The 3 mutations resulting in the severe EBS Dowling-Meara type (2 in KRT14 and 1 in KRT5) are in the highly conserved amino or carboxyl ends of the rod domain. The KRT14 mutation in the family with the less severe Koebner type (148066.0001) is in a less conserved region of the rod domain.
In contrast with mutations affecting the central alpha-helical rod domain of keratin-14, which are found in association with epidermolysis bullosa simplex in its various clinical forms, NFJS/DPR-associated mutations were found in a region of the gene encoding the nonhelical head (E1/V1) domain and were found to result in very early termination of translation (Lugassy et al., 2006). The data suggested that KRT14 plays an important role during ontogenesis of dermatoglyphics and sweat glands. Among other functions, the N-terminal part of keratin molecules confers protection against proapoptotic signals. Ultrastructural examination of patient skin biopsy specimens provided evidence for increased apoptotic activity in the basal cell layer where KRT14 is expressed, suggesting that apoptosis is an important mechanism in the pathogenesis of NFJS/DPR.
In transgenic mice, Vassar et al. (1991) showed that a mutant KRT14 gene, which was driven by the normal human KRT14 enhancer/promoter at the 5-prime end and encoded a truncated keratin molecule lacking 135 amino acids from its carboxyl terminus, resulted in abnormalities resembling the group of genetic disorders known as epidermolysis bullosa simplex (e.g., 131950, 131900).
In mapping studies, McAlpine (1990) used the symbols KRT14L1, KRT14L2, and KRT14L3 because of the uncertainty as to which of the hybridizing bands represent active gene(s).
Rosenberg et al. (1988) determined that 2 genes encoding K16 (148067) and 3 genes encoding K14 are clustered in 2 distinct segments of chromosome 17. The genes within each cluster were found to be tightly linked. By in situ hybridization, one cluster of genes was located at band 17p12-p11 and a second at band 17q12-q21. Small clusters of grains were also noted on the long arm of chromosome 14 at bands q31-q32 and on the long arm of chromosome 21. These may have represented sites of more distantly related keratin genes.
In a family with generalized epidermolysis bullosa simplex of the Koebner type (EBS1B; 131900), Bonifas et al. (1991) demonstrated linkage of the disorder to the gene encoding keratin-14. Further studies demonstrated a T-to-C substitution at bp 3542 in exon 6 resulting in a change of amino acid 384 from leucine to proline. The mutation created a new MspI site. It is notable that finding the particular mutation was a 'stroke of luck.' No polymorphism of the KRT14 gene was known and linkage of EBS to DNA markers in the family in question were inconclusive. Bonifas et al. (1991), however, hybridized a 3-prime untranslated KRT14 probe to DNA from members of the family digested with 9 restriction endonucleases. This revealed the unique MspI restriction site change which was tightly linked to EBS in this family with a lod score of 3.0. It was found in all affected members and in no unaffected members. Vassar et al. (1991) produced basal keratinocyte fragility causing neonatal death in mice carrying a transgene encoding a shortened KRT14. The phenotype of the human disease caused by the leu384-to-pro mutation is much less severe than that caused by deletion of 135 amino acids from the KRT14 carboxyl terminus in the transgenic mice.
Epidermolysis bullosa simplex, severe type (EBS1A; 131760), formerly known as the Dowling-Meara type, is distinguished from other subtypes not only by its severity but also by the presence of large cytoplasmic clumps of tonofilaments that can be labeled with antibodies against the basal epidermal keratins. In 2 patients with the Dowling-Meara form, Coulombe et al. (1991) demonstrated critical mutations in the KRT14 gene. One patient had a C-to-T transition corresponding to nucleotide 433 of the gene, converting an arginine residue (CGC) to a cysteine residue (TGC) at amino acid 125 (R125C), located near the amino end of the KRT14 rod segment. To demonstrate the effect on function, Coulombe et al. (1991) engineered the arg125-to-cys mutation in a KRT14 cDNA and showed that this cDNA disrupted keratin network formation in transfected keratinocytes and disturbed filament assembly in vitro. Also see 148066.0003.
Sasaki et al. (1999) reported that the arg125-to-cys mutation had been identified in 4 of 6 Japanese families with the Dowling-Meara type of EBS. They stated that 8 of 19 families with mutations in the KRT14 gene carried the arg125-to-cys mutation.
Hut et al. (2000) identified a de novo heterozygous R125C mutation in 2 patients with EBS Dowling-Meara type.
Ma et al. (2001) used differential interference contrast microscopy to show that the arg125-to-cys mutation in the KRT14 gene greatly reduced the ability of reconstituted mutant filaments to bundle under crosslinking conditions, possibly causing the fragility of epithelial cells seen in some keratin-based disorders.
From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 2 patients who were heterozygous for the R125C mutation in the KRT14 gene.
In an Italian male infant with generalized severe EB simplex and a hoarse cry with mild inspiratory stridor, Diociaiuti et al. (2020) identified heterozygosity for the recurrent R125C mutation in the KRT14 gene. The mutation arose de novo in the proband.
In a second patient with epidermolysis bullosa simplex of the Dowling-Meara type (EBS1A; 131760), Coulombe et al. (1991) demonstrated a G-to-A transition converting an arginine residue (CGC) to a histidine residue (CAC) at amino acid 125 (R125H). Also see 148066.0002.
Although laryngeal involvement is generally associated with junctional forms of EB, Shemanko et al. (2000) reported 2 unrelated infants with no family history of skin disease who presented within hours of birth with extensive blistering of the skin and oral mucosa and subsequently developed hoarse cries. One had a de novo heterozygous type 14 keratin mutation (arg125 to his), consistent with a diagnosis of Dowling-Meara EBS. The other had a heterozygous type 5 keratin mutation (ser181 to pro; 148040.0012).
Hut et al. (2000) identified a de novo heterozygous R125H mutation in a patient with EBS Dowling-Meara type.
From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 4 patients who were heterozygous for the R125H mutation in the KRT14 gene. In addition, 1 patient was heterozygous for R125H in KRT14 and an R471C variant in the KRT5 gene. Detailed clinical information was not reported for that patient.
In 2 French sibs, born of consanguineous parents, with autosomal recessive epidermolysis bullosa (EBS1D; 601001), Hovnanian et al. (1993) identified a homozygous 491A-C transversion in the KRT14 gene, resulting in a glu144-to-ala (E144A) substitution in the first helical segment of the rod domain. The loss of an ionic interaction with keratin 5 was thought to affect KRT14-KRT5 heterodimer formation. Genetic linkage with keratin 5 was excluded. The parents were unaffected.
In a family with at least 16 affected individuals in 5 generations with localized epidermolysis bullosa simplex of the Weber-Cockayne type (EBS1C; 131800), in which nonscarring blisters are limited to the hands and feet, Chen et al. (1993) found deletion of 3 nucleotides in the KRT14 gene, resulting in deletion of a glutamic acid residue from the helix 2B region of the gene product.
In a patient with severe autosomal recessive epidermolysis bullosa simplex (EBS1D; 601001), Chan et al. (1994) identified a homozygous 612T-A transversion in the KRT14 gene, resulting in a tyr204-to-ter (Y204X) substitution. Each of the unaffected parents, who were related, was heterozygous for the mutation. Skin biopsy of the patient showed lack of a discernible keratin filament network in basal epidermal cells.
In a large 3-generation Irish family (TCDG) with the generalized simplex (Koebner) form of epidermolysis bullosa (EBS1B; 131900), originally reported by Humphries et al. (1990) as family TCD-EBS2, Humphries et al. (1993) identified a c.3028T-G transversion in the KRT14 gene, resulting in a met272-to-arg (M272R) substitution within the central rod domain in the linker region.
Jonkman et al. (1996) studied a kindred with autosomal recessive epidermolysis bullosa simplex (EBS1D; 601001) in which affected members lacked expression of keratin-14 and showed homozygosity for a acceptor splice site mutation that resulted in skipping of exon 2 in 24% of the KRT14 transcripts and to the use of a cryptic splice site in 76% of the transcripts. Clinically the patients had severe generalized skin blistering that improved slightly with age. The basal cells of the patient did not express keratin 14 and contained no keratin intermediate filaments. The expression of keratin 5, the obligate copolymer of keratin 14, was slightly reduced. The expression of keratin 15, the alternative basal cell keratin, was increased, suggesting upregulation or stabilization to compensate for the lack of keratin 14. The expression of keratin 16, keratin 17, and keratin 19 was not different from controls. The homozygous mutation identified by Jonkman et al. (1996) was located at the 3-prime acceptor splice site of intron 1 where nucleotide 1840 showed an A-to-C transversion in the affected individuals. Premature termination codons were generated in all transcripts at either codon 175+1 or codon 175+29, leading to a keratin-14 protein truncated within the helical 1B rod domain. Heterozygous family members were unaffected. The disorder was associated with circumscribed hyperkeratotic lesions with the histology of epidermolytic hyperkeratosis.
Shemanko et al. (1998) described a heterozygous T-to-C transition in the KRT14 gene, resulting in a met119-to-thr (M119T) substitution, in a patient with an EBS Dowling-Meara phenotype (EBS1A; 131760) with severe palmoplantar hyperkeratosis. The patient was a 41-year-old man whose case had been included previously in 2 brief reports. He had widespread skin fragility and blistering from birth. From early childhood he developed gross palmoplantar hyperkeratosis resulting in flexion contractures of the hands and considerable functional and cosmetic difficulties. The patient's sibs and parents were clinically normal.
In a 3-year-old boy (family 1) with generalized severe EBS and a hoarse cry, Cummins et al. (2001) identified heterozygosity for a de novo c.416T-C transition in exon 1 of the KRT14 gene, resulting in the previously reported M119T substitution within the highly conserved helix initiation motif of the alpha-helical rod. The authors noted that the proband experienced early onset of unusually severe palmoplantar hyperkeratosis, similar to the 41-year-old man with the M119T variant reported by Shemanko et al. (1998).
In 2 French boys (patients 1 and 2) with generalized severe EB simplex who developed marked palmoplantar keratoderma in the first months of life, Titeux et al. (2006) identified heterozygosity for the M119T substitution in the KRT14 gene, which occurred de novo in both probands. Immunocytochemistry in patient keratinocytes revealed numerous KRT14 filament aggregates after hypoosmotic shock, whereas none were seen in control cells.
See also M119I (148066.0010) and M119V (148066.0022) for other mutations affecting the same codon. Noting the distinct EBS phenotypes resulting from different substitutions at the M119 residue, Cummins et al. (2001) suggested that a more severe phenotype might result from greater perturbation of coiled-coil interactions by replacement of the hydrophobic methionine with hydrophilic threonine, whereas with conversion to isoleucine or valine, hydrophobicity is maintained.
In a patient with localized EBS of the Weber-Cockayne type (EBS1C; 131800), Chen et al. (1995) found a 417G-A transition in the KRT14 gene, resulting in a met119-to-ile (M119I) substitution.
Hu et al. (1997) reported a large 6-generation French-Portuguese family (Ta) with localized EBS (EBS1C) due to a heterozygous M119I mutation. Blistering began around 1 year of age and was limited to the hands and feet. There was disease exacerbation in the summer, and the disorder tended to decrease with age.
See also M119T (148066.0009) and M119V (148066.0022) for other mutations affecting the same codon. Noting the distinct EBS phenotypes resulting from different substitutions at the M119 residue, Cummins et al. (2001) suggested that a more severe phenotype might result from greater perturbation of coiled-coil interactions by replacement of the hydrophobic methionine with hydrophilic threonine, whereas with conversion to isoleucine or valine, hydrophobicity is maintained.
Homozygosity for M119I
In the family with EBS1C reported by Hu et al. (1997), one family member, born of a consanguineous union, was homozygous for the mutation. This patient had a more severe phenotype, with earlier onset, more generalized blistering, and involvement of the oral, vaginal, and anal mucosa. Since age 14, blistering has been limited to the hands and feet. The distal skin was scarred, all 10 toenails were missing, and small areas of palmar hyperkeratosis were present. Hu et al. (1997) concluded that this mutation acts as a 'partial dominant' in that heterozygotes have milder localized disease and homozygotes have a more severe disease.
In a patient with generalized epidermolysis bullosa simplex of the Koebner type (EBS1B; 131900), Hut et al. (2000) identified a de novo heterozygous T-to-C transition at nucleotide 3634 (c.3634T-C) in exon 6 of the KRT14 gene resulting in a tyr415-to-his (Y415H) mutation in the helix termination motif of the keratin-14 rod domain 2B. The mutation was identified using a restriction enzyme strategy to eliminate a KRT14 pseudogene that complicates KRT14 mutation detection in genomic DNA.
In a patient with Dowling-Meara epidermolysis bullosa simplex (EBS1A; 131760), Hut et al. (2000) identified a de novo heterozygous T-to-A transversion at nucleotide position 3647 (c.3647T-A) in exon 6 of the KRT14 gene, resulting in a leu419-to-gln (L419Q) mutation in the helix termination motif of the keratin-14 rod domain 2B. The mutation was identified using a restriction enzyme strategy to eliminate a KRT14 pseudogene that complicates KRT14 mutation detection in genomic DNA.
In 2 patients with the Weber-Cockayne type of epidermolysis bullosa simplex (EBS1C; 131800), Hut et al. (2000) identified a heterozygous G-to-A transition at nucleotide position 3655 (c.3655G-A) in exon 6 of the KRT14 gene resulting in a glu422-to-lys (E422K) mutation in the helix termination motif of the keratin 14 rod domain 2B. The mutation was identified using a restriction enzyme strategy to eliminate a KRT14 pseudogene that complicates KRT14 mutation detection in genomic DNA.
In a child, born of consanguineous Pakistani parents, with a mild form of autosomal recessive epidermolysis bullosa simplex (EBS1D; 601001), Batta et al. (2000) reported a homozygous mutation (92delT) in codon 31 of the KRT14 gene. This mutation causes a frameshift that results in a premature termination codon further downstream in exon 1 and was predicted to encode a protein of 116 amino acids, of which the first 30 are identical to the normal KRT14 sequence and the remaining 86 residues are missense sequence. There was complete absence of KRT14 in the epidermis and the child exhibited only mild to moderate disease. The unaffected mother was heterozygous for the mutation. The K14-negative basal epidermal cells from the patient stained positively for K15 (148030), suggesting that upregulation of expression of K15 may have compensated for the loss of K14.
In the historic multigenerational Swiss family in which Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000) was first reported by Naegeli (1927), with follow-up by Franceschetti and Jadassohn (1954) and Itin et al. (1993), Lugassy et al. (2006) found a heterozygous frameshift mutation in the KRT14 gene: a heterozygous guanosine deletion at position 17 (17delG) of the KRT14 cDNA sequence (numbering starting from the initiation codon). This mutation was predicted to result in a frameshift and to generate a stop codon 8 amino acids downstream of the mutation site.
Studying a family from the United States with the diagnosis of dermatopathia pigmentosa reticularis (DPR; 125595), first reported by Heimer et al. (1992), Lugassy et al. (2006) demonstrated a heterozygous C-to-A transversion at cDNA position 54 of KRT14, resulting in the nonsense mutation cys 18 to ter (C18X).
In a patient, born of consanguineous parents, with a severe form of generalized epidermolysis bullosa (EBS1D; 601001), Rugg et al. (1994) identified a homozygous 2-bp deletion (313_314del) in the KRT14 gene, resulting in premature termination. The was no KRT14 expression in the skin and no intermediate filaments were seen in the basal cells of the epidermis. Each unaffected parent was heterozygous for the mutation.
In 4 unrelated probands (patients 1, 12, 15, and 18) with Dowling-Meara EBS (EBS1A; 131760), Pfendner et al. (2005) identified a heterozygous mutation in the KRT14 gene, resulting in an asn123-to-ser (N123S) substitution. The mutation was shown to have occurred de novo in each case. All of the patients had severe generalized blistering with oral mucous membrane involvement. The affected residue is within the 1A domain of the molecule and was predicted to severely perturb the intermediate filament network.
From a cohort of 33 newborns with generalized severe EBS who were reported to the National Health Service of the UK over a 15-year period and underwent genetic analysis, Sathishkumar et al. (2016) identified 2 patients who were heterozygous for the N123S mutation in the KRT14 gene.
In affected members of 3 families from the United Kingdom with Naegeli-Franceschetti-Jadassohn syndrome (NFJS; 161000), Lugassy et al. (2006) identified heterozygosity for a C-to-T transition in the KRT14 gene that resulted in a gln7-to-ter (Q7X) substitution within the E1/V1 (head) domain. The mutation segregated fully with the disorder in each family, and haplotype analysis suggested that NFJS in these 3 families might be caused by a founder mutation.
In an Iranian male proband (family 10) with generalized severe skin blistering and extensive palmoplantar keratoderma (EBS1A; 131760), Vahidnezhad et al. (2016) identified heterozygosity for a de novo in-frame 18-bp deletion (c.1241del18) in exon 6 of the KRT14 gene, resulting in deletion of 6 amino acids within the 2B domain.
In a Scottish proband (family 15) with skin blistering limited to the hands and feet (EBS1C; 131800), Rugg et al. (2007) identified heterozygosity for a c.1130T-C transition in the KRT14 gene, resulting in an ile377-to-thr (I377T) substitution near the stutter region within helix 2B. Skin biopsy revealed keratin aggregates, and the cleavage plane was through the cytoplasm of the basal keratinocytes. The proband was the only family member examined, and familial segregation was not reported.
In a large Iranian family (family 9) in which 14 members over 4 generations experienced mild skin blistering limited to the palms and soles, Vahidnezhad et al. (2016) identified heterozygosity for the I377T mutation in KRT14.
Homozygosity for I377T
Three family members in family 9 reported by Vahidnezhad et al. (2016), who were born of consanguineous unions and exhibited more generalized lesions, were found to be homozygous for the I377T variant. The authors designated this family as having a 'semidominant' mode of inheritance.
In 5 affected members over 3 generations (family 2) with the Koebner type of EBS (EBS1B; 131900), Cummins et al. (2001) identified heterozygosity for a c.415A-G transition in the KRT14 gene, resulting in a met119-to-val (M119V) substitution at a residue within the highly conserved helix initiation motif of the alpha-helical rod. The mutation was not found in 3 unaffected family members.
See also M119T (148066.0009) and M119I (148066.0010) for other mutations affecting the same codon. Noting the distinct EBS phenotypes resulting from different substitutions at the M119 residue, Cummins et al. (2001) suggested that a more severe phenotype might result from greater perturbation of coiled-coil interactions by replacement of the hydrophobic methionine with hydrophilic threonine, whereas with conversion to isoleucine or valine, hydrophobicity is maintained.
In a 31-year-old Japanese woman with the Koebner type of EBS (EBS1B; 131900), Gu et al. (2002) identified heterozygosity for a c.1231G-T transversion in the KRT14 gene, resulting in a glu411-to-ter (E411X) substitution at a residue in the 'g' position, which stabilizes the coiled-coil by forming salt bridges. The truncated protein lacks the last 16 amino acid residues of the helix termination peptide 2B and the entire tail domain. DNA was unavailable from the proband's affected sons, but the mutation was not found in 50 unrelated control DNA samples.
In a 2-year-old French boy (patient 3) with generalized severe EB simplex (EBS1A; 131760), Titeux et al. (2006) identified heterozygosity for a de novo 1-bp deletion (c.1246delC) in exon 6 of the KRT14 gene, causing a frameshift resulting in a premature termination codon (Arg416AlafsTer26) and a protein lacking the helix termination peptide and the tail domain.
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